MND1 enables homologous recombination in somatic cells primarily outside the context of replication

Faithful and timely repair of DNA double‐strand breaks (DSBs) is fundamental for the maintenance of genomic integrity. Here, we demonstrate that the meiotic recombination co‐factor MND1 facilitates the repair of DSBs in somatic cells. We show that MND1 localizes to DSBs, where it stimulates DNA repair through homologous recombination (HR). Importantly, MND1 is not involved in the response to replication‐associated DSBs, implying that it is dispensable for HR‐mediated repair of one‐ended DSBs. Instead, we find that MND1 specifically plays a role in the response to two‐ended DSBs that are induced by irradiation (IR) or various chemotherapeutic drugs. Surprisingly, we find that MND1 is specifically active in G2 phase, whereas it only marginally affects repair during S phase. MND1 localization to DSBs is dependent on resection of the DNA ends and seemingly occurs through direct binding of MND1 to RAD51‐coated ssDNA. Importantly, the lack of MND1‐driven HR repair directly potentiates the toxicity of IR‐induced damage, which could open new possibilities for therapeutic intervention, specifically in HR‐proficient tumors.